Objective To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19–associated ARDS.
Design, Setting, and Participants Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.
Interventions Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).
Main Outcomes and Measures The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.
Results A total of 299 patients (mean [SD] age, 61  years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, −1.16; 95% CI, −1.94 to −0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.
Conclusions and Relevance Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days
In this randomized clinical trial involving 299 adults with moderate or severe ARDS due to COVID-19, dexamethasone plus standard care compared with standard care alone significantly increased the number of days alive and free of mechanical ventilation during the first 28 days. Dexamethasone was not associated with increased risk of adverse events in this population of critically ill COVID-19 patients.
This trial included only patients with COVID-19 and moderate or severe ARDS and provided laboratory, physiological, and adverse events data on the use of corticosteroids in this population. The ventilator-free days criterion was chosen as the primary outcome because it comprises both mortality and ventilation duration in surviving patients. The number of days alive and free from mechanical ventilation at 28 days was significantly lower than reported in other trials of non–COVID-19 ARDS,but consistent with COVID-19 ARDS studies, confirming the disease severity. The difference between groups of 2.26 days was lower than the effect size of 3 days used in the sample size calculation. This reduction is relevant in the context of a pandemic, in which an inexpensive, safe, and widely available intervention like dexamethasone increases even modestly the number of ventilator-free days and may reduce the risk of ventilatory complications, ICU length of stay, and burden to the health care system.
Mortality rates were high and not significantly different between groups, in contrast with the RECOVERY trial of dexamethasone in patients hospitalized for COVID-19and a trial of dexamethasone in patients with non-COVID-19 ARDS.The high mortality rate might be explained by several factors. The patients had a high risk of death as shown by the low mean Pao2:Fio2 ratio and mean SAPS III score of 70, which represents a mortality risk of 70.9% in South America.In a previous randomized clinical trial, moderate to severe ARDS not caused by COVID-19 had an elevated mortality rate in Brazil of 52%, and recent data collected by Brazilian Association of Critical Care demonstrated mortality rates of 66% to 70% for ventilated patients with COVID-19 in Brazilian ICUs.This may be explained by the pandemic and its burden to the health care system, especially in a country with limited resources like Brazil. However, even in high-income countries the mortality rate in ventilated patients with COVID-19 might range from 54% to 88%.This mortality rate may be similar to that of other low and middle-income countries and is important to consider when translating the scientific evidence to clinical practice. In this sense, the results of this trial expand those of the RECOVERY trial by showing that corticosteroids were effective even when the baseline mortality rate was high.
The dexamethasone dose was chosen based on a previous trial showing the benefit of dexamethasone to patients with non–COVID-19 ARDS. Previous data suggest that high doses of corticosteroids (the equivalent of 30 mg/d of dexamethasone) in viral pneumonia may be associated with unfavorable outcomes.However, there are no currently available data from patients with COVID-19 to determine if higher doses are harmful. In the present study, the number of adverse events, new infections, and the use of insulin were comparable in both groups, in line with previous studies that did not demonstrate an augmented risk of adverse events with corticosteroids in non-COVID-19 ARDS.
This trial has several strengths. Bias was controlled by ensuring allocation concealment, all patients were analyzed according to their randomization group, and follow-up was complete. Also, adverse events data regarding corticosteroid use among patients with COVID-19 were provided, along with detailed data on ventilatory parameters, ARDS treatment, and laboratory and physiological variables.
This study has several limitations. First, it was an open-label trial due to time constraints of producing placebo in a pandemic scenario with an urgent need for reliable and randomized data. Second, 35% of the patients in the control group received corticosteroids during the study period, possibly related to the open-label design, the disease severity of the patients, and other diverse indications for corticosteroid use in critical care.However, the use of corticosteroids in the control group would have biased the results toward the null, and the study identified a benefit of the intervention on the primary outcome. Third, the open-label design and investigator-reported data on adverse events and infections may have led to bias in the description of these events. Fourth, the trial was underpowered for important secondary outcomes like mortality and the study was interrupted before the original sample size was obtained due to external evidence of benefit, and the obtained sample size was limited to demonstrate benefits in secondary outcomes.
In patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care, compared with standard care alone, resulted in a statistically significant increase increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days
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